Consistent with NIMH's Research Domain Criteria initiative (Insel & Cuthbert, 2009), the primary research goal is to advance the development of neurobiological measures of anxiety spectrum disorder, defining quantitative dimensions of pathology that advance understanding of the anxiety diathesis. The work's focus is the brain's amygdala-centered fear/defense circuit, as defined by basic laboratory neuroscience, which mediates a range of obligatory survival reflexes, including the potentiated startle response, and is generally held to be hyper-active in anxiety disorders. Our previous research indicates, however, that anxiety patients differ widely in their reflex reactivity during fear memory imagery (Cuthbert et al., 2003; Lang et al., 2005, 2007; Lang & McTeague, 2009). While most phobic patients show marked increases in probe startle magnitude during fear imagery, a high percentage of patients with more generalized anxiety disorders fail to show significant potentiation. Paradoxically, fear potentiation decreases progressively as the disorder is more severe, co-morbid, with greater negative affect-despite verbal reports of high, often much higher, fear during imagery (McTeague et al., 2009, 2010). Thus, we hypothesize a spectrum-wide, diagnosis cross-cutting dimension of fear-circuit regulation/dysregulation, and here use social anxiety disorder as a model system to elucidate the phenomenon, studying healthy controls and three social anxiety subtypes: circumscribed, generalized, and generalized social anxiety with depression, assessing circuit function directly with functional Magnetic Resonance Imaging (fMRI) as it relates to reflex reactivity in the psychophysiology laboratory. The specific aims are 1) to determine if activation of fear/defense circuit structures and their functional connectivity differ in response to narrative imagery challenges across social anxiety subtypes; 2) to directly assess the relationship between reflex reactivity and fear/defense circuit activatio patterns and a clinical symptom picture characterized by high co-morbidity, chronicity, and high negative affect; 3) to more broadly evaluate potential differences in emotional reactivity across social anxiety subtypes by assessing appetitive, as well as defensive reactivity using fMRI and psychophysiology, and 4) to evaluate the prognostic value of reflex and fear/defense circuit bio-markers measured during in initial assessment in predicting questionaire-based outcome measures of clinical status following treatment. PUBLIC HEALTH RELEVANCE: Currently, the diagnosis of anxiety disorder depends almost entirely on patient-interview and the clinician's assessment the patient's symptom report. The clinician has available no neurobiological measures of anxiety disorder-as when an internist orders an electro- cardiogram of the heart to help interpret a patient's report of chest pain. The proposed research explores quantitative measures of brain function and reflex reactivity that could define a dimension of anxiety disorder severity, and thus potentially enhance the clinician's understanding of the patient, improving diagnosis significantly and guiding new treatments.